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Scaparrotta et al. Multidisciplinary Respiratory Medicine 2012, 7:13
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REVIEW
Open Access
Montelukast versus inhaled corticosteroids in the
management of pediatric mild persistent asthma
Alessandra Scaparrotta1*, Sabrina Di Pillo1, Marina Attanasi1, Daniele Rapino1, Anna Cingolani1,
Nicola Pietro Consilvio1, Marcello Verini1 and Francesco Chiarelli2
Abstract
International guidelines recommend the use of inhaled corticosteroids (ICSs) as the preferred therapy, with
leukotriene receptor antagonists (LTRAs) as an alternative, for the management of persistent asthma in children.
Montelukast (MLK) is the first LTRA approved by the Food and Drug Administration for the use in young asthmatic
children.
Therefore, we performed an analysis of studies that compared the efficacy of MLK versus ICSs. We considered
eligible for the inclusion randomized, controlled trials on pediatric populations with Jadad score > 3, with at least
4 weeks of treatment with MLK compared with ICS.
Although it is important to recognize that ICSs use is currently the recommended first-line treatment for asthmatic
children, MLK can have consistent benefits in controlling asthmatic symptoms and may be an alternative in children
unable to use ICSs or suffering from poor growth. On the contrary, low pulmonary function and/or high allergic
inflammatory markers require the corticosteroid use.
Keywords: Childhood asthma, Inhaled corticosteroids, Leukotriene receptor antagonist, Montelukast
Review
Bronchial asthma is a chronic inflammatory disease
characterized by airway hyperresponsiveness and respiratory symptoms (breathlessness, wheezing, chest
tightness and coughing) [1,2] and the involvement of
numerous cell types (eosinophils, T cells, mast cells,
basophils and neutrophils) in triggering airway inflammation [3].
Antileukotrienes are a new class of anti-inflammatory
drugs, which include Montelukast (MLK), Pranlukast,
Zafirlukast and Zileuton, with an important glucocorticoids sparing effects. These drugs interfere either with
leukotriene receptors (leukotriene receptor antagonists or
LTRAs) or with leukotriene production (5- lipoxygenase
inhibitors) [4].
Leukotrienes are important proinflammatory mediators in asthma. These eicosanoids are derived from the
metabolism of membrane phospholipids within alveolar
macrophages, eosinophils, mast cells and neutrophils,
* Correspondence: [email protected]
1
Allergy and Respiratory Unit, Department of Pediatrics, G. D’Annunzio
University of Chieti, Via Dei Vestini 5, Chieti 66013, Italy
Full list of author information is available at the end of the article
that are involved in the pathophysiology of this disease
[5]. Cysteinyl leukotrienes cause bronchoconstriction,
mucus secretion, increased vascular permeability and
eosinophil migration to the airways, and also promote
smooth muscle proliferation. Their synthesis and release
appear not to be blocked by corticosteroid therapy [6-12].
MLK is a selective cysteinyl - leukotriene receptor antagonist that reduces asthmatic inflammation and airway
resistance and prevents bronchoconstriction [3,13-15]. It
is the most studied and used LTRA in pediatric age,
being the first approved by the Food and Drug Administration (FDA) for the use in young asthmatic children, at
the dosage of 4 mg for children aged from 1 to 5 years
and of 5 mg for patients 6 to 14 years of age once daily
[16].
It was foreseen that antileukotrienes could be used as
the first line agents in the management of mildmoderate persistent asthma. A Cochrane review (last
updated in January 2004) summarized the accumulating
evidence derived from 13 randomized controlled trials
and concluded that low doses of inhaled glucocorticoids
were superior to LTRAs [4].
© 2012 Scaparrotta et al.; licensee BioMed Central Ltd. This is an Open Access article distributed under the terms of the
Creative Commons Attribution License (http://creativecommons.org/licenses/by/2.0), which permits unrestricted use,
distribution, and reproduction in any medium, provided the original work is properly cited.
Scaparrotta et al. Multidisciplinary Respiratory Medicine 2012, 7:13
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All current international guidelines recommend the
use of low-dose (200–400 mcg) of beclomethasone
(BDP) or equivalent inhaled corticosteroids (ICSs) as the
preferred controller therapy, with LTRAs as an alternative, for the management of persistent asthma in children
(5–11 years of age) and adolescents. In patients unresponsive to ICSs alone, the alternative options are the
addition of LTRAs or long-acting beta-agonist (LABA),
or an increase of ICS dosage [17-20].
Also the pediatric PRACTALL guidelines (PRACTicing
ALLergology) [21], in agreement with the GINA (The
Global Initiative for Asthma) [18] and the BTS-SIGN
(British Thoracic Society Scottish Intercollegiate Guidelines Network) [20] guidelines, indicate ICSs as the first
choice for controller therapy of pediatric asthma. The
authors of BTS-SIGN guidelines recommend the use of
LTRA, if ICS cannot be administered. MLK is the most
commonly used in children [22].
ICSs are used as medication for early intervention and
long-term management of childhood asthma, because
they directly reach the airways and intensively inhibit airways inflammation [23-25]. However, when the amount
of drug deposited in the respiratory tract increases with
using higher doses, the risks of adverse drug reactions
also increase [3,26].
Antileukotrienes have the advantage of being administered orally in a single or twice daily doses and seem to
lack the adverse effects on growth, bone mineralisation
and on the adrenal axis, associated with long-term systemic glucocorticoid therapy [4]. In general, few patients
experienced adverse events during clinical trials with
MLK. Headache was the most frequent adverse event; in
pediatric patients treated for 8 weeks, diarrhoea, laryngitis, pharyngitis, nausea, otitis, sinusitis and viral infections occurred in more than 2% of MLK recipients and
were more prevalent in MLK-treated patients than in
placebo recipients [5].
The preference for ICSs is primarily based on evidence from trials comparing mean responses between a
treatment group and a control group; however, there is
increased appreciation of the considerable interindividual variability in response to ICSs and LTRAs [27-38].
Thus it is important to provide information that can
guide the clinician in selecting the most likely medication to achieve a favourable response for particular
patients.
Few studies have addressed the factors that determine
the marked variability in response to asthma control
therapy. It is unknown, for example, whether patients
who do not respond well to one medication might respond to another medication [39].
This article reviewed results from randomized, controlled trials of children with mild-moderate asthma in
order to assess the usefulness of MLK in the management
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of persistent asthma compared to the preferred therapy
with ICSs.
Methods
A PubMed search indexed for MEDLINE was undertaken until December 2010, using the keywords “montelukast or leukotriene receptor antagonist and mild
persistent pediatric asthma” and “montelukast or leukotriene receptor antagonist versus inhaled corticosteroids”, utilizing in the search the limit for age “all child”
and/or “randomized controlled trials”.
No time limits were imposed in the search. We have
selected 16 randomized, controlled trials performed from
2001 to 2008 on pediatric populations in which LTRAs
were compared to ICSs, making a distinction according to
MLK efficacy in studies that observed similar results of the
two drugs versus others that observed a minor efficacy of
MLK compared to ICSs (Tables 1 and 2).
Inclusion criteria for trials comprised: 1) randomized
controlled trials; 2) children aged less than 18 years with
a clinical diagnosis of asthma; 3) a minimum of 4 weeks
of treatment with MLK compared with ICS; 4) Jadad
score [54] > 3; 5) clinical and pulmonary function improvements as outcomes. References of relevant articles were
analyzed.
Results
Not inferior efficacy of Montelukast compared to Inhaled
Corticosteroids
Maspero et al. in a 6-month, open-label extension study
compared the efficacy of oral MLK with inhaled BDP
(IBDP). A total of 124 out of 266 asthmatic children, 6
to 11 years of age, enrolled in the base study, entered a
6-month open-label extension study (74 boys, 50 girls)
and were re-randomized (2:1 ratio) to receive once-daily
oral MLK (n = 83) or IBDP 100 mcg three times daily
(n = 41). Children and their parents showed a significantly higher overall satisfaction for MLK at 6 months
than for IBDP (p = 0.001 and p < 0.05, respectively); they
thought that MLK was more convenient (p < 0.001) and
less difficult to use (p = 0.005). Oral corticosteroid use
was similar in the MLK (13% of patients) and IBDP
(17%) treatment groups. There was a higher compliance
of patients in the MLK group. The two study groups
were similar in safety, change in forced expiratory
volume in 1 s (FEV1), asthma-related medical resource
utilization, school absenteeism and parental work loss.
So MLK was considered by the authors as a safe and
effective asthma treatment regimen to which children
with asthma are more likely to adhere. Conflict of interest was not declared [40].
Another study supporting the similar effectiveness of
MLK and ICSs in controlling mild to moderate chronic
asthma is that of Williams et al. Treatment with both
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Table 1 Studies that demonstrated similar efficacy of MLK compared to ICS
First author, year [ref]
Study duration
Patients (Age)
Drugs doses
Results
Maspero, 2001 [40]
6 months
124 pts (6–11 years)
MLK = 5 mg /d
Higher satisfaction for MLK vs IBPD
with higher compliance. Similar: oral CS
use, safety, FEV1 change, asthma-related
medical resource utilization, school
absenteeism, parental work loss.
IBDP = 300 μg /d
Williams, 2001 [41]
37 weeks
112 pts (6–14 years)
Stelmach, 2002 [42]
8 weeks
91 pts (12 ± 1.7 years)
MLK = 5 mg /d
IBDP = 300 μg /d
TRC = 400 μg /d
MLK = 5 mg/d
FMT = 24 μg /d
Karaman, 2004 [43]
14 weeks
63 pts (8–14 years)
MLK = 5 mg /d
IBD = 400 μg /d
Similar improvement in multiple
parameters of asthma control and in
daytime symptom scores.
With TRC and MLK: IL-10 level
increased, EOS and ECP levels
significantly decreased, all clinical
parameters improved, with no significant
difference in clinical score improvement.
MLK improvement: airway obstruction,
DSS, β2-a use, nocturnal awakenings,
asthma exacerbations, ULKE4 levels.
MLK + IBD
Stelmach, 2005 [44]
6 months
51 pts (6–18 years)
IBD = 400 μg /d
IBD = 800 μg /d
MLK = 5 mg/d
Garcia Garcia, 2005 [45]
12 months
994 pts (6–14 years)
MLK = 5 mg/d
FP = 100 μg /d
Kumar, 2007 [46]
12 weeks
62 pts (5–15 years)
IBD = 400 μg/d
MLK = 5 mg/d
Stelmach, 2007 [47]
4 weeks
87 pts (6–18 years)
MLK = 5–10 mg /d
IBD = 200 μg /d
ICS (high dose) and MLK significantly
decreased total and specific IgE levels.
Clinical score/FEV1 significantly
improved with medium (p = 0.002) and
high dose (p = 0.001) of IBD and MLK
(p = 0.002).
Significantly greater improvement of
RFDs with FP vs MLK, but inferior to
the limits (−7%) fixed for judging MLK
inferior to FP, so MLK was not inferior
to FP in % of asthma RFDs because the
adjusted difference was −2.8%.
The median % predicted FEV1 was
similar in the two groups (p = 0.44),
similar improvement in clinical symptom
scores; no significant difference in the
need for rescue drugs.
Lung function improved significantly in all
groups, with no significant difference in
improvement.
MLK + IBD
Kooi, 2008 [48]
3 months
63 pts (2–6 years)
MLK = 4 mg/day
FP = 200 μg/d
Placebo
FP had beneficial effect on symptoms (vs
placebo, p = 0.021), MLK on EOS vs
placebo (p = 0.045). No differences
between FP and MLK in lung function
parameters, except for FOT.
β2-a, β2 agonist; DSS, daily symptom scores; ECP, eosinophil cationic protein; EOS, eosinophil blood counts; FEV1, forced expiratory volume in 1 s; FMT, formoterol;
FOT, Forced Oscillation Tecnique; FP, fluticasone propionate; IBD, inhaled budesonide; IBDP, inhaled beclomethasone; ICS, inhaled corticosteroids; MLK,
montelukast; pts, patients; RFDs, rescue-free days; TRC, triamcinolone ULKE4, urinary leukotriene E4.
MLK and ICSs resulted in improvement in multiple parameters of asthma control in 112 children (aged 6–14 years)
treated for 37 weeks with IBDP (100 mcg 3 times daily)
and MLK (5 mg/daily). Improvements in daytime symptom scores were generally comparable among treatment
groups. This study was sponsored by Merck [41].
In three study (2002, 2005, 2007), Stelmach et al. found
no statistical significant differences between MLK and
ICSs in clinical and functional parameters in children
(6–18 years) treated for 8 weeks, 6 months and 4 weeks
respectively. In the first one (91 children) the authors
found that after treatment with inhaled triamcinolone
(Azmacort, Aventis) and MLK the level of IL-10 in blood
serum significantly increased, eosinophil blood counts
and ECP levels significantly decreased and all clinical
parameters improved [42]. In the second one (51 children) they observed that: a high dose of inhaled corticosteroid and MLK significantly decreased levels of total
and specific IgE; clinical score and FEV1 significantly
improved after treatment with medium (p = 0.002) and
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Table 2 Studies that demonstrated inferiority of MLK compared to ICS
First author, year [ref]
Study duration
Patients (Age)
Drugs doses
Results
Stelmach, 2004 [49]
4 weeks
256 pts (6–18 years)
MLK = 5–10 mg /d
With TRC and MLK, FEV1 and
PC20 significantly increased; mean
total symptoms score and EOS
significantly decreased. TRC had a
stronger effect on PC20 than MLK
and in reduction in β2-a use, similar
improvement in clinical symptoms.
TRC = 400 μg /d
Ostrom, 2005 [16]
12 weeks
342 pts (6–12 years)
MLK = 5 mg/d
FP = 100 μg/d
Szefler, 2005 [39]
8 weeks
144 pts (6–17 years)
MLK = 5–10 mg/d
FP = 200 μg/d
Zeiger, 2006 [50]
8 weeks
144 pts (6–17 years)
MLK = 5–10 mg/d
FP = 200 μg/d
Sorkness, 2007 [51]
48 weeks
285 pts (6–14 years)
MLK = 5 mg/d
FP = 200 μg/d
PACT = FP 100
μg + LABA 100 μg/d
Knuffman, 2009 [52]
48 weeks
191 pts (6–14 years)
MLK = 5 mg /d
FP = 200 μg /d
PACT combination =
FP 100 μg +
LABA 100 μg/d
Szefler, 2007 [53]
52 weeks
395 pts (2–8 years)
MLK = 4–5 mg /d
BD = 0,5 mg /d
FP (vs MLK) significantly increased %
change from baseline FEV1, PEF, %
RFDs and reduced night time symptom
scores and β2-a use.
FEV1 improvement was 6.8% for FP
and 1.9% for MLK (mean difference
4,9%, p = <0,001). ICS therapy is
better if low pulmonary function and
high levels of allergic inflammation
markers.
Significantly greater improvement in
ACDs/week with FP than MLK (p =
0.001). Clinical outcomes, pulmonary
responses and inflammatory
biomarkers improved significantly more
with FP than with MLK.
Significantly greater improvement with
FP vs MLK (p = 0.004). FP group
had a longer time to first prednisone
burst and to a treatment failure, fewer
treatment failure, better FEV1,
FEV1/FVC, PEF, PC20, symptoms
score and lower eNO level than MLK
group.
A history of parental asthma best
predicted the expected treatment
benefit with FP vs MLK in terms of
gain in ACDs and time to first
exacerbation; elevated baseline eNO
predicted response for FP regarding
the gain in ACDs; prior ICS use and
low PC20 each predicted the expected
treatment benefit with FP over MLK
regarding time to first exacerbation.
Both treatments provided acceptable
asthma control; however, peak flow
and caregiver and Physician Global
Assessments favored IBD.
ACD, asthma control days; β2-a, β2 agonist; eNO, exhaled nitric oxide; EOS, eosinophil blood counts; FEV1, forced expiratory volume in 1 s; FP, fluticasone
propionate; IBD, inhaled budesonide; ICS, inhaled corticosteroids; LABA, long-acting beta-agonist; MLK, montelukast; PEF, peak expiratory flow; pts, patients; RFDs,
rescue-free days; TRC, triamcinolone.
high dose (p = 0.001) of inhaled budesonide and MLK
(p = 0.002). There were no differences between groups in
changes of all clinical parameters after treatment [44]. In
the third one (87 children), they demonstrated a significant improvement of lung function in all treatment
groups. Conflict of interest was not declared [47].
Karaman et al. performed a randomized, 14-week,
2-period, prospective parallel group study in 63 clinically
stable outpatients aged 8 to 14 years with a history of
mild persistent asthma for at least 1 year. Conflict of
interest was not declared. They observed that likewise to
inhaled budesonide (IBD), MLK produced improvement
in airway obstruction, daily symptom scores, total daily
as-needed β-agonist use, nocturnal awakenings, percentage of days and of patients with asthma exacerbations.
So, the authors concluded that MLK may be a welltolerated and effective therapeutic option in 8 to 14year-old patients with mild persistent asthma [43].
The MOSAIC study (MLK Study of Asthma in Children, sponsored by Merck & Co.) was designed to assess
if MLK (5 mg daily, for 12 months) was inferior to
inhaled fluticasone propionate (100 mcg 2 times daily,
for 12 months) in asthma symptom control [45]. The
primary endpoint was the percentage of asthma rescue-
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free days (RFDs, without rescue medication or asthmarelated health care utilization). The two treatments
would be considered equivalent if the upper limit of the
95% confidence interval for the difference in the primary
endpoint (mean percentages of RFDs) was above −7%.
The main conclusion of this study performed on 994
children was that MLK was not inferior to inhaled fluticasone propionate (IFP) in increasing the percentage of
rescue-free days, because the adjusted difference was
−2.8% (< 1 day per month). The secondary end points
(FEV1 value, days with β2-agonist use, and quality of life)
were significantly better in the IFP group, although
improved in both groups. In the MLK group there was a
major use of systemic corticosteroids (18%) than in the
IFP group (11%, p < 0.001). Both treatments were welltolerated. This study has the criticism that, although the
authors calculated the non inferiority interval on the
basis of prior studies and before recruitment, the number of asthma rescue-free days clearly showed a difference in favour of IFP (p value not presented) [55,56].
In the study of Kumar et al. MLK demonstrated consistent benefit in controlling symptoms of asthma. The
median (95% confidence interval) percentage predicted
FEV1 was similar for ICSs and MLK after 12 weeks of
treatment: FEV1 = 76.70 (67.96–90.53) % for IBD; FEV1 =
75 (67.40–88.47) % for MLK (p = 0.44). There was similar improvement also in clinical symptom scores and not
statistically significant difference between the groups in
the need for rescue drugs as well as side effects reported
by parents [46].
The study of Kooi et al. [48] was the first, and to date,
the only randomized control trial which included preschool children (2–6 years). Conflict of interest was not
declared. The study sample was too small, so statistical
β-error cannot be excluded. During the study period
daily symptom score (DSS) improved in all groups, with
statistically significant difference only between IFP and
placebo in favour of the first one. This result could be
influenced by the higher DSS baseline mean values of
the IFP group (3.68) vs MLK group (1.58) (p = 0.02).
No differences in DSS final values and in the score of
rescue medication use between groups were found. A
significant reduction in circulating eosinophils was
found in the MLK group only (p = 0.008), which was
significantly different from the change found in the
placebo group (p = 0.045). So the authors concluded
that IFP had a beneficial effect on symptoms and MLK
on blood eosinophil level as compared to placebo.
Except for a difference in one lung function parameter
(frequency dependence, measured by Forced Oscillation Tecnique) after 3 months between IFP and MLK
in favour of the IFP group, this study revealed no differences between the two drugs on respiratory function
improvement [22].
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Minor efficacy of Montelukast compared to Inhaled
Corticosteroids
In contrast with the findings in the other studies, Stelmach et al. in three-arm, randomized no blinding or placebo pragmatic trial compared the effect of a 4-week
monotherapy with low-dose of triamcinolone acetonide
(400 mcg/day), inhaled nedocromil and MLK on clinical
parameters of asthma (score, FEV1), bronchial hyperreactivity (PC20/Hystamine), and eosinophil blood count.
256 children, aged 6–18 yr, with mild to moderate
asthma, participated in an 8-week study. The study
showed the strongest effect of low-dose inhaled steroids on clinical symptoms, lung function, bronchial
hyperreactivity and eosinophil blood count when
compared to other asthma medications. Conflict of
interest was not declared [49].
Ostrom et al. [16] in a controlled study sponsored by a
pharmaceutical company (GlaxoSmithKline Inc.) compared the efficacy, safety, health outcomes and costeffectiveness of three-months treatments of IFP (50 mcg 2
times daily) versus MLK (5 mg daily) in 342 children (6 to
12 years of age) with persistent asthma. Compared with
MLK, IFP significantly increased mean percent change
from baseline FEV1 (p = 0.002), morning PEF (peak expiratory flow) (p = 0.004), evening PEF (p = 0.020), and percent
rescue-free days (p = 0.002) at end point, and it significantly reduced night time symptom scores (p < 0.001) and
mean total (p = 0.018), and night time (p < 0.001) albuterol
use. Parents and physicians satisfaction was higher with
IFP [16]. The safety profiles of these drugs were comparable. The costs of the IFP treatments were only one third
of those of the MLK treatment [55].
The CLIC study (Characterizing the Response to a
Leukotriene Receptor Antagonist and an Inhaled Corticosteroid), sponsored by the National Heart, Lung,
and Blood Institute, USA, was an independently
funded controlled study that compared the efficacy of
ICS and MLK [39,50]. An eight-week cross-over design was used to compare IFP (100 mcg 2 times daily)
with MLK (5 mg daily). The main aim of the study
was to find predictive factors for a favourable response to either drugs. Improvements in most clinical
asthma control measures were seen with both controllers, but all clinical outcomes, pulmonary responses
(the mean percentage of improvement in FEV1 was
7% for IFP and 2% for MLK, p < 0.001), and inflammatory bio-markers improved significantly more with
IFP than with MLK treatment. A favourable response
to IFP alone (23% of subjects) was associated with
higher levels of eNO (exhaled nitric oxide), total eosinophil counts, higher levels of serum IgE and higher
levels of serum eosinophil cationic protein, and lower
levels of methacholine PC20 (the provocation concentration of inhaled methacholine that causes a 20%
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decrease in FEV1) and decreased pulmonary function
values. A favourable response to MLK alone (5% of
subjects) was associated with lower age and shorter
disease duration. Finally, greater differential response
to IFP over MLK was associated with higher bronchodilator use, bronchodilator response, eNO levels and
eosinophil cationic protein levels, lower methacholine
PC20 and pulmonary function values [55].
When asthma control days (ACDs) were used as an
outcome, higher baseline eNO levels, greater salbutamol
use, and more positive aeroallergen skin test responses,
in addition to fewer ACDs at baseline, predicted more
ACDs variations after IFP treatment [50,55]. For MLK
no predictor, except fewer ACDs at baseline, was associated with more ACDs during treatment. Higher eNO
levels at baseline was the only baseline characteristic discriminating the ACD response to treatments and was
positively associated with greater ACD responses to IFP
than to MLK. No difference in adherence to medications
was found, but dropouts were more common in the
MLK group. The authors concluded that asthma therapy
may soon move from the current approach, based on
mean responses in populations, to one in which the
treatment that is the most likely to rapidly produce a
favourable response is identified in each individual patient on the basis of their phenotypic and, possibly genotypic, characteristics [55].
The PACT study (Pediatric Asthma Controller Trial),
sponsored by the National Heart, Lung, and Blood Institute, was another independently funded controlled study,
in which a total of 285 children (ages 6–14 years) with
mild to moderate persistent asthma were randomized to 1
of 3 double-blind 48-week treatments: IFP 100 mcg twice
daily, IFP 100 mcg/salmeterol 50 mcg in the morning and
salmeterol 50 mcg in the evening (PACT combination),
and MLK 5 mg in the evening. The outcomes included
asthma control days (primary outcome), exacerbations,
humanistic measurements, and pulmonary function measurements. IFP monotherapy and PACT combination were
comparable in many patient-measured outcomes, including percent of asthma control days, but IFP monotherapy
was superior for clinic-measured FEV1/forced vital capacity (p = 0.015), maximum bronchodilator response
(p = 0.009), eNO (p < 0.001), and methacholine PC20 (p
< 0.001). IFP monotherapy was superior to MLK for
asthma control days (64.2% vs 52.5%; p = 0.004) and for all
other control outcomes [51].
Another independent study sponsored by the National
Heart, Lung, and Blood Institute tried to identify phenotypic characteristics retaining predictive value for the difference in treatment responses between twice daily IFP and
once-daily MLK. Data from the Pediatric Asthma Controller Trial (PACT) were assessed with multivariate analysis.
The authors concluded that physicians treating children
Page 6 of 9
with parental history of asthma, elevated eNO, low methacholine PC20, or history of ICS use can expect the best
long-term outcomes with ICS therapy, as compared to
treatment with LTRAs [52].
Another study of Szefler et al. (sponsored by AstraZeneca) compared the long-term efficacy and safety of
budesonide inhalation suspension and MLK in children
2 to 8 years old with mild asthma or recurrent wheezing
randomized to once-daily budesonide inhalation suspension 0.5 mg or once-daily oral MLK 4 or 5 mg for
52 weeks. No significant differences between-group were
observed for time to first additional asthma medication
at 52 weeks; however, time to first additional asthma
medication was longer at 12 weeks and exacerbation
rates were lower over a period of 52 weeks for budesonide versus MLK. Time to first severe exacerbation (requiring oral corticosteroids) was similar in both groups,
but the percentage of subjects requiring oral corticosteroids over a period of 52 weeks was lower with budesonide (25.5% vs 32.0%). Peak flow and caregiver and
Physician Global Assessments favoured budesonide [53].
Discussion
The PRACTALL consensus report [21] recommends
ICSs as the first-line treatment for persistent asthma, for
their capacity to improve symptoms, lung function, airway hyperresponsiveness and to reduce frequency and
severity of asthma exacerbations. Atopy and poor lung
function predict a favourable response to ICSs [39]. ICSs
have potent anti-inflammatory effects in asthmatic airways and, in particular, they reduce eosinophilic airway
inflammation.
If control is inadequate on a low dose after 1–2 months,
reasons for poor control should be identified and , if indicated, an increased ICS dose or additional therapy with
LTRAs or LABA should be considered. It has been known
for many years that the effect of ICSs in older children
begins to disappear as soon as treatment is discontinued
[57]. New evidences do not support a disease-modifying
role after cessation of treatment with ICSs in preschool
children [21,58-60].
About LTRAs, this consensus [21] establish that they
are an alternative first-line treatment for persistent
asthma, because evidences support the use of oral MLK
as an initial controller therapy for mild asthma in children [6], as it provides bronchoprotection [61] and it
reduces airway inflammation as measured by eNO levels
in some preschool children with allergic asthma [62,63].
Younger age (< 10 years) and high levels of urinary leukotrienes predict a favourable response to LTRA [39].
MLK is a useful therapy also as add-on therapy to ICS,
as the mechanisms of action of the two drugs are different and complementary [37]. Benefit has been shown in
children as young as 6 months of age [63,64]. MLK can
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be a good treatment for viral-induced wheeze, to reduce
the frequency of exacerbations in young children aged
2–5 years [65,66] and there is some evidence that they
may be beneficial in the 0–2 age group [21,63].
First line or add-on treatment of oral MLK in preschool
children with mild to moderate asthma and elevated eNO,
decreases eNO levels and improves airway responsiveness,
lung function and symptom scores [67].
However ICSs are the current mainstay of treatment in
patients with persistent asthma. Several studies, comparing the efficacy of ICSs and LTRAs in patients with persistent asthma, have demonstrated overall greater efficacy
of low-dose ICSs for most outcomes of asthma control [16,39,49-53,68-70]. ICSs improve lung function
and airway responsiveness to inhaled methacholine,
which is the most widely used method of measuring
airway hyperresponsiveness in patients with asthma
[39,50-52,68,71,72].
However, there is variability in the individual responses
of asthmatic patients to these classes of antiasthmatic
drugs: higher bronchodilator use, increased bronchodilator responsiveness, higher eNO and eosinophil cationic
protein levels, greater airway hyperresponsiveness and
pulmonary function values are associated with a greater
response to ICS treatment in children. Indeed some
authors identified characteristics of patients that should
guide the clinician in the choice of asthma control medication: children who have reduced pulmonary function
or high levels of markers indicating allergic inflammation
should receive ICS therapy [39,68].
As about a quarter of the patients may benefit more
from MLK than IFP, therapy with this LTRA could be
useful in children with mild-non atopic asthma and/or
mainly exercise-induces symptoms [55] and in children
with decelerated or poor growth.
Inhibition of linear growth (height) in children has
been observed with the administration of ICSs, especially
with dosage > 200 mcg/daily [6,57,73-76].
MLK is the first antileukotriene agent available for
children 2 to 5 years of age with persistent asthma; it has
shown efficacy as a preventive treatment for asthma in a
number of clinical trials in children aged 2 to 14 years.
The onset of action of MLK is rapid as significant
improvements in daytime symptoms are recorded within
1 day. Clinical trials data suggest that MLK effectively
counteracts exercise-induced bronchoconstriction and
provides protection against bronchoconstriction induced
by hyperventilation with cold dry air in 3 to 5 year-old
children [77].
Asthma control and pulmonary and inflammatory response improve consistently and significantly also with
MLK. Various studies compared its efficacy versus ICSs,
without finding clinical and functional differences between drugs [40-48].
Page 7 of 9
Important issues to consider in the treatment of preschool children with asthma are the ease of drug administration and the long-term tolerability of therapy,
because treatment is typically chronic. Inhalants are the
most commonly prescribed controller therapies; however, very young patients may have difficulty using
inhaled corticosteroids and dose delivery can be variable
[78-80]. Moreover, reduced compliance with inhalants
for asthma compared to orally administered therapy has
been reported [6,81].
To optimize beneficial effects from therapy and asthma
control, it is very important to adopt a “patient-centered”
treatment, i.e. a close relationship between physician and
patient, so that the latter can discuss and understand the
disease and express preferences for the diagnostic and
therapeutic item. Such a relationship implies also that the
outcomes are more patient-focused and representative of
the patient’s feelings, perceptions and wishes, so enhancing
patient adherence to treatment and therapeutic effectiveness [82].
One potential advantage of MLK is the ease of administering a once-daily chewable tablet. Moreover, no tachyphylaxis or change in the safety profile is evident after up
to 140 weeks of MLK therapy in adults and 80 weeks of
MLK therapy in pediatric patients aged 6 to 14 years
[6,83,84].
Conclusions
Although it is important to recognize that the use of ICSs
is currently the recommended first-line treatment for children with asthma, many studies discussed in this article
suggest that MLK can have consistent benefit in controlling asthmatic symptoms and may be an alternative, safe,
orally administered, non steroidal agent for treating mild
persistent asthma, especially in younger children unable to
use ICS, not compliant, or victims of adverse effects, or
suffering from poor growth. On the contrary, low pulmonary function and/or high allergic inflammatory markers require the corticosteroid use.
Competing interests
The authors declare that they have no competing interests.
Author details
1
Allergy and Respiratory Unit, Department of Pediatrics, G. D’Annunzio
University of Chieti, Via Dei Vestini 5, Chieti 66013, Italy. 2Department of
Pediatrics, University of Chieti, G. D’Annunzio University of Chieti, Via Dei
Vestini 5, Chieti 66013, Italy.
Received: 11 June 2012 Accepted: 5 July 2012
Published: 5 July 2012
References
1. Gibson PG, Wlodarczyk JW, Hensley MJ, Gleeson M, Henry RL, Cripps AW,
Clancy RL: Epidemiological association of airway inflammation with
asthma symptoms and airway hyperresponsiveness in childhood. Am J
Respir Crit Care Med 1998, 158:36–41.
Scaparrotta et al. Multidisciplinary Respiratory Medicine 2012, 7:13
http://www.mrmjournal.com/content/7/1/13
2.
3.
4.
5.
6.
7.
8.
9.
10.
11.
12.
13.
14.
15.
16.
17.
18.
19.
20.
21.
22.
23.
24.
25.
Maddox L, Schwartz DA: The pathophysiology of asthma. Ann Rev Med
2002, 53:477–498.
Kondo N, Katsunuma T, Odajima Y, Morikawa A: A randomized open-label
comparative study of montelukast versus theophylline added to inhaled
corticosteroid in asthmatic children. All Int 2006, 55:287–293.
Ducharme F, Di Salvio F: Antileukotriene agents compared to inhaled
corticosteroids in the management of recurrent and/or chronic asthma
in adults and children. Cochrane Database Syst Rev 2004, 1:CD002314.
Jarvis B, Markham A: Montelukast: a review of its therapeutic potential in
persistent asthma. Drugs 2000, 59:891–928.
Knorr B, Franchi LM, Bisgaard H, Vermeulen JH, LeSouef P, Santanello N,
Michele TM, Reiss TF, Nguyen HH, Bratton DL: Montelukast, a leukotriene
receptor antagonist, for the treatment of persistent asthma in children
aged 2 to 5 years. Pediatrics 2001, 108:E48.
Busse WW: The role of leukotrienes in asthma and allergic rhinitis. Clin
Exp Allergy 1996, 26:868–879.
Laitinen LA, Laitinen A, Haahtela T, Vilkka V, Spur BW, Lee TH: Leukotriene
E4 and granulocytic infiltration into asthmatic airways. Lancet 1993,
341:989–990.
Dahlén SE, Hedquist P, Hammerstrom S, Samuelsson B: Leukotrienes are
potent constrictors of human bronchi. Nature 1980, 288:484–486.
Drazen JM, Israel E, O’Byrne PM: Treatment of asthma with drugs
modifying the leukotriene pathway. N Engl J Med 1999, 340:197–206.
Cohen P, Noveral JP, Bhala A, Nunn SE, Herrick DJ, Grunstein MM:
Leukotriene D4 facilitates airway smooth muscle cell proliferation via
modulation of the IGF axis. Am J Physiol 1995, 269:L151–L157.
Dworski R, Fitzgerald GA, Oates JA, Sheller JR: Effect of oral prednisone on
airway inflammatory mediators in atopic asthma. Am J Respir Crit Care
Med 1994, 149:953–959.
Mechiche H, Naline E, Candenas L, Pinto FM, Birembault P, Advenier C,
Devillier P: Effects of cysteinyl leukotrienes in small human bronchus and
antagonist activity of montelukast and its metabolites. Clin Exp Allergy
2003, 33:887–894.
Pizzichini E, Leff JA, Reiss TF, Hendeles L, Boulet LP, Wei LX, Efthimiadis AE,
Zhang J, Hargreave FE: Montelukast reduces airway eosinophilic inflammation
in asthma: a randomized, controlled trial. Eur Respir J 1999, 14:12–18.
Villaran C, O’Neill SJ, Helbling A, van Noord JA, Lee TH, Chuchalin AG,
Langley SJ, Gunawardena KA, Suskovic S, Laurenzi M, Jasan J, Menten J, Leff
JA: Montelukast versus salmeterol in patients with asthma and
exercise-induced bronchoconstriction. Montelukast/Salmeterol Exercise
Study Group. J Allergy Clin Immunol 1999, 104:547–553.
Ostrom NK, Decotiis BA, Lincourt WR, Edwards LD, Hanson KM, Carranza
Rosenzweig JR, Crim C: Comparative efficacy and safety of low-dose
fluticasone propionate and montelukast in children with persistent
asthma. J Pediatr 2005, 147:213–20.
Castro-Rodriguez JA, Rodrigo GJ: The role of inhaled corticosteroids and
montelukast in children with mild-moderate asthma: results of a
systematic review with meta-analysis. Arch Dis Child 2010, 95:365–370.
Global Initiative for Asthma: Global Strategy for Asthma Management and
Prevention. 2007. www: ginasthma.com.
National Heart, Lung, and Blood Institute: Expert Panel Report 3: Guidelines for
de Diagnosis and Management of Asthma. Bethesda, MD. National Institutes of
Health. 2007. www.nhlbi.nih.gov.
Management of asthma: British Thoracic Society Scottish Intercollegiate
Guidelines Network. Thorax 2008, 63:1–121.
Bacharier LB, Boner A, Carlsen KH, Eigenmann PA, Frischer T, Götz M, Helms
PJ, Hunt J, Liu A, Papadopoulos N, Platts-Mills T, Pohunek P, Simons FE,
Valovirta E, Wahn U, Wildhaber J: European Pediatric Asthma Group. The
European Pediatric Asthma Group. Diagnosis and treatment of asthma in
childhood: a PRACTALL consensus report. Allergy 2008, 63:5–34.
Miceli Sopo S, Onesimo R, Radzik D, Scala G, Cardinale F: Montelukast
versus inhaled corticosteroids as monotherapy for prevention of asthma:
which one is best? Allergol Immunopathol 2009, 37:26–30.
Nishima S, Furusho K: Japanese Society of Pediatric Allergy and Clinical
Immunology New pediatric guideline for the treatment and
management of bronchial asthma in Japan. Pediatric Int 2003, 45:
759–766.
Bhalay G, Sandham DA: Recent advances in corticosteroids for the
treatment of asthma. Curr Opin Investig Drugs 2002, 3:1149–1156.
Lipworth BJ: Clinical pharmacology of corticosteroids in bronchial
asthma. Pharmacol Ther 1993, 58:173–209.
Page 8 of 9
26. Allen DB, Bielory L, Derendorf H, Dluhy R, Colice GL, Szefler SJ: Inhaled
corticosteroids: past lessons and future issues. J Allergy Clin Immunol 2003,
112(3 Suppl):S1–S40.
27. National Asthma Education and Prevention Program: Expert Panel Report:
Guidelines for the Diagnosis and Management of Asthma Update on
Selected Topics-2002. J Allergy Clin Immunol 2002, 110(5 Suppl):S141–219.
28. Lee TH, Brattsand R, Leung DY: Corticosteroid action and resistance in
asthma. Am J Respir Cell Mol Biol 1996, 93:S1–S79.
29. Sher ER, Leung DY, Surs W, Kam JC, Zieg G, Kamada AK, Szefler SJ: Steroidresistant asthma. Cellular mechanisms contributing to inadequate
response to glucocorticoid therapy. J Clin Invest 1994, 93:33–39.
30. Leung DY, Bloom JW: Update on glucocorticoid action and resistance.
J Allergy Clin Immunol 2003, 111:3–22.
31. Malmstrom K, Rodriguez-Gomez G, Guerra J, Villaran C, Piñeiro A, Wei LX,
Seidenberg BC, Reiss TF: Oral montelukast, inhaled beclomethasone, and
placebo for chronic asthma. A randomized, controlled trial. Montelukast/
Beclomethasone Study Group. Ann Intern Med 1999, 130:487–495.
32. Zhang J, Yu C, Holgate ST, Reiss TF: Variability and lack of predictive ability
of asthma end-points in clinical trials. Eur Respir J 2002, 20:1102–1109.
33. Szefler SJ, Martin RJ, King TS, Boushey HA, Cherniack RM, Chinchilli VM, Craig
TJ, Dolovich M, Drazen JM, Fagan JK, Fahy JV, Fish JE, Ford JG, Israel E, Kiley
J, Kraft M, Lazarus SC, Lemanske RF Jr, Mauger E, Peters SP, Sorkness CA:
Asthma Clinical Research Network of the National Heart Lung, and Blood
Institute. Significant variability in response to inhaled corticosteroids for
persistent asthma. J Allergy Clin Immunol 2002, 109:410–418.
34. Palmer LJ, Silverman ES, Weiss ST, Drazen JM: Pharmacogenetics of asthma.
Am J Respir Crit Care Med 2002, 165:861–866.
35. Israel E, Chervinsky PS, Friedman B, Van Bavel J, Skalky CS, Ghannam AF, Bird
SR, Edelman JM: Effects of montelukast and beclomethasone on airway
function and asthma control. J Allergy Clin Immunol 2002, 110:847–854.
36. Meyer KA, Arduino JM, Santanello NC, Knorr BA, Bisgaard H: Response to
montelukast among subgroups of children aged 2 to 14 years with
asthma. J Allergy Clin Immunol 2003, 111:757–762.
37. Simons FE, Villa JR, Lee BW, Teper AM, Lyttle B, Aristizabal G, Laessig W,
Schuster A, Perez-Frias J, Sekerel BE, Menten J, Leff JA: Montelukast added
to budesonide in children with persistent asthma: a randomized, doubleblind, crossover study. J Pediatr 2001, 138:694–698.
38. Simons FE, Menton J, Leff JA: New drug treatment for asthma: clinical
versus statistical significance. J Pediatr 2002, 140:484–485.
39. Szefler SJ, Phillips BR, Martinez FD, Chinchilli VM, Lemanske RF, Strunk RC,
Zeiger RS, Larsen G, Spahn JD, Bacharier LB, Bloomberg GR, Guilbert TW,
Heldt G, Morgan WJ, Moss MH, Sorkness CA, Taussig LM: Characterization
of within-subject responses to fluticasone and montelukast in childhood
asthma. J Allergy Clin Immunol 2005, 115:233–242.
40. Maspero JF, Dueñas-Meza E, Volovitz B, Pinacho Daza C, Kosa L, Vrijens F,
Leff JA: Oral montelukast versus inhaled beclomethasone in 6 to 11-year
old children with asthma: results of an open-label extension study
evaluating long-term safety, satisfaction, and adherence to therapy. Curr
Med Res Opin 2001, 17:96–104.
41. Williams B, Noonan G, Reiss TF, Knorr B, Guerra J, White R, Matz J: Long-term
asthma control with oral montelukast and inhaled beclomethasone for
adults and children 6 years and older. Clin Exp Allergy 2001, 31:845–854.
42. Stelmach I, Jerzynska J, Kuna P: A randomized, double-blind trial of the
effect of glucocorticoid, antileukotriene and β-agonist treatment on IL-10
serum levels in children with asthma. Clin Exp Allergy 2002, 32:264–269.
43. Karaman Ö, Sünneli L, Uzuner N, Islekel H, Turgut CS, Köse S, Tezcan D,
Coker C, Erbayraktar Z: Evaluation of montelukast in 8 to 14 year old
children with mild persistent asthma and compared with inhaled
corticosteroids. Allergol Immunopathol 2004, 32:21–27.
44. Stelmach I, Bobrowska-Korzeniowska M, Majak P, Stelmach W, Kuna P: The
effect of montelukast and different doses of budesonide on IgE serum
levels and clinical parameters in children with newly diagnosed asthma.
Pulm Pharmacol Ther 2005, 18:374–380.
45. Garcia Garcia ML, Wahn U, Gilles L, Swern A, Tozzi CA, Polos P: Montelukast,
compared with fluticasone, for control of asthma among 6- to
14-year-old patients with mild asthma: the MOSAIC study. Pediatrics 2005,
116:360–369.
46. Kumar V, Ramesh P, Lodha R, Pandey RM, Kabra SK: Montelukast vs. inhaled
low-dose budesonide as monotherapy in the treatment of mild
persistent asthma: a randomized double blind controlled trial. J Trop
Pediatr 2007, 53:325–330.
Scaparrotta et al. Multidisciplinary Respiratory Medicine 2012, 7:13
http://www.mrmjournal.com/content/7/1/13
47. Stelmach I, Grzelewski T, Bobrowska-Korzeniowska M, Stelmach P, Kuna P: A
randomized, double-blind trial of the effect of anti-asthma treatment on
lung function in children with asthma. Pulm Pharmacol Ther 2007, 20:691–700.
48. Kooi EM, Schokker S, Marike Boezen H, de Vries TW, Vaessen-Verberne AA,
van der Molen T, Duiverman EJ: Fluticasone or montelukast for preschool
children with asthma-like symptoms: Randomized controlled trial. Pulm
Pharmacol Ther 2008, 21:798–804.
49. Stelmach I, Majak P, Jerzynska J, Stelmach W, Kuna P: Comparative effects
of triamcinolone, nedocromil and montelukast on asthma control in
children. A randomized pragmatic study. Pediatr Allergy Immunol 2004,
15:359–364.
50. Zeiger RS, Szefler SJ, Phillips BR, Schatz M, Martinez FD, Chinchilli VM,
Lemanske RF Jr, Strunk RC, Larsen G, Spahn JD, Bacharier LB, Bloomberg GR,
Guilbert TW, Heldt G, Morgan WJ, Moss MH, Sorkness CA, Taussig LM:
Childhood Asthma Research and Education Network of the National
Heart, Lung, and Blood Institute. Response profiles to fluticasone and
montelukast in mild-to-moderate persistent childhood asthma. J Allergy
Clin Immunol 2006, 117:45–52.
51. Sorkness CA, Lemanske RF, Mauger DT, Boehmer SJ, Chinchilli VM, Martinez FD,
Strunk RC, Szefler SJ, Zeiger RS, Bacharier LB, Bloomberg GR, Covar RA, Guilbert
TW, Heldt G, Larsen G, Mellon MH, Morgan WJ, Moss MH, Spahn JD, Taussig
LM: Childhood Asthma Research and Education Network of the National
Heart, Lung, and Blood Institute. Long-term comparison of 3 controller
regimens for mild-moderate persistent childhood asthma: the Pediatric
Asthma Controller Trial. J Allergy Clin Immunol 2007, 119:64–72.
52. Knuffman JE, Sorkness CA, Lemanske RF Jr, Mauger DT, Boehmer SJ,
Martinez FD, Bacharier LB, Strunk RC, Szefler SJ, Zeiger RS, Taussig LM:
Childhood Asthma Research and Education Network of the National
Heart, Lung, and Blood Institute. Phenotypic predictors of long-term
response to inhaled corticosteroid and leukotriene modifier therapies in
pediatric asthma. J Allergy Clin Immunol 2009, 123:411–416.
53. Szefler SJ, Baker JW, Uryniak T, Goldman M, Silkoff PE: Comparative study of
budesonide inhalation suspension and montelukast in young children
with mild persistent asthma. J Allergy Clin Immunol 2007, 120:1043–1050.
54. Jadad AR, Moore RA, Carroll D, Jenkinson C, Reynolds DJ, Gavaghan DJ,
McQuay HJ: Assessing the quality of reports of randomized clinical trials:
is blinding necessary? Control Clin Trials 1996, 17:1–12.
55. Jartti T: Inhaled corticosteroids or montelukast as the preferred primary
long-term treatment for pediatric asthma? Eur J Pediatr 2008, 167:731–736.
56. Goodman DC: When an asthma drug has an inferiority complex: a
noninferiority trial. Pediatrics 2005, 116:493–495.
57. Simons FE: A comparison of beclomethasone, salmeterol, and placebo in
children with asthma. Canadian Beclomethasone DipropionateSalmeterol Xinafoate Study Group. N Engl J Med 1997, 337:1659–1665.
58. Guilbert TW, Morgan WJ, Zeiger RS, Mauger DT, Boehmer SJ, Szefler SJ,
Bacharier LB, Lemanske RF Jr, Strunk RC, Allen DB, Bloomberg GR, Heldt G,
Krawiec M, Larsen G, Liu AH, Chinchilli VM, Sorkness CA, Taussig LM,
Martinez FD: Long-term inhaled corticosteroids in preschool children at
high risk for asthma. N Engl J Med 2006, 354:1985–1997.
59. Bisgaard H, Hermansen MN, Loland L, Halkjaer LB, Buchvald F: Intermittent
inhaled corticosteroids in infants with episodic wheezing. N Engl J Med
2006, 354:1998–2005.
60. Murray CS, Woodcock A, Langley SJ, Morris J, Custovic A: IFWIN study team.
Secondary prevention of asthma by the use of Inhaled Fluticasone
propionate in Wheezy Infants (IFWIN): double-blind, randomised,
controlled study. Lancet 2006, 368:754–762.
61. Bisgaard H, Nielsen KG: Bronchoprotection with a leukotriene receptor
antagonist in asthmatic preschool children. Am J Respir Crit Care Med
2000, 162:187–190.
62. Straub DA, Minocchieri S, Moeller A, Hamacher J, Wildhaber JH: The effect
of montelukast on exhaled nitric oxide and lung function in asthmatic
children 2 to 5 years old. Chest 2005, 127:509–514.
63. Straub DA, Moeller A, Minocchieri S, Hamacher J, Sennhauser FH, Hall GL,
Wildhaber JH: The effect of montelukast on lung function and exhaled
nitric oxide in infants with early childhood asthma. Eur Respir J 2005,
25:289–294.
64. van Adelsberg J, Moy J, Wei LX, Tozzi CA, Knorr B, Reiss TF: Safety,
tolerability, and exploratory efficacy of montelukast in 6- to 24-monthold patients with asthma. Curr Med Res Opin 2005, 21:971–979.
65. Bisgaard H, Zielen S, Garcia-Garcia ML, Johnston SL, Gilles L, Menten J, Tozzi
CA, Polos P: Montelukast reduces asthma exacerbations in 2- to
Page 9 of 9
66.
67.
68.
69.
70.
71.
72.
73.
74.
75.
76.
77.
78.
79.
80.
81.
82.
83.
84.
5-year-old children with intermittent asthma. Am J Respir Crit Care Med
2005, 171:315–322.
Bisgaard H: Study Group on Montelukast and Respiratory Syncytial VirusA
randomized trial of montelukast in respiratory syncytial virus postbronchiolitis. Am J Respir Crit Care Med 2003, 167:379–383.
Moeller A, Lehmann A, Knauer N, Albisetti M, Rochat M, Johannes W: Effects
of montelukast on subjective and objective outcome measures in
preschool asthmatic children. Pediatr Pulmonol 2008, 43:179–186.
O’Byrne PM, Gauvreau GM, Murphy DM: Efficacy of leukotriene receptor
antagonists and synthesis inhibitors in asthma. J Allergy Clin Immunol
2009, 124:397–403.
Busse W, Raphael GD, Galant S, Kalberg C, Goode-Sellers S, Srebro S,
Edwards L, Rickard K: Fluticasone Proprionate Clinical Research Study
Group. Low-dose fluticasone propionate compared with montelukast for
first-line treatment of persistent asthma: a randomized clinical trial. J
Allergy Clin Immunol 2001, 107:461–468.
Bleecker ER, Welch MJ, Weinstein SF, Kalberg C, Johnson M, Edwards L,
Rickard KA: Low-dose inhaled fluticasone propionate versus oral
zafirlukast in the treatment of persistent asthma. J Allergy Clin Immunol
2000, 105:1123–1129.
Juniper EF, Kline PA, Vanzieleghem MA, Ramsdale EH, O'Byrne PM,
Hargreave FE: Long-term effects of budesonide on airway responsiveness
and clinical asthma severity in inhaled steroid-dependent asthmatics. Eur
Respir J 1990, 3:1122–1127.
Kanniess F, Richter K, Böhme S, Jörres RA, Magnussen H: Montelukast
versus fluticasone: effects on lung function, airway responsiveness and
inflammation in moderate asthma. Eur Respir J 2002, 20:853–858.
The Childhood Asthma Management Program Research Group: Long term
effect of budesonide or nedocromil in children with asthma. N Engl J
Med 2000, 343:1054–1063.
The Childhood Asthma Management Program (CAMP): Design, rationale,
and methods. Childhood Asthma Management Program Research Group.
Control Clin Trials 199, 20:91–120.
Doull IJ, Freezer NJ, Holgate ST: Growth of prepubertal children with mild
asthma treated with inhaled beclomethasone dipropionate. Am J Respir
Crit Care Med 1995, 151:1715–1719.
Pedersen S: Do inhaled corticosteroids inhibit growth in children? Am J
Respir Crit Care Med 2001, 164:521–535.
Muijsers RBR, Noble S: Montelukast: a review of its therapeutic potential
in asthma in children 2 to 14 years of age. Paediatr Drugs 2002,
4:123–139.
Janssens HM, Devadason SG, Hop WC, LeSouëf PN, De Jongste JC, Tiddens
HA: Variability of aerosol delivery via spacer devices in young asthmatic
children in daily life. Eur Respir J 1999, 13:787–791.
Barnes N: Relative safety and efficacy of inhaled corticosteroids. J Allergy
Clin Immunol 1998, 101:S460–S464.
Bisgaard H: Delivery of inhaled medication to children. J Asthma 1997,
34:443–467.
Kelloway JS, Wyatt RA, Adlis SA: Comparison of patients’ compliance with
prescribed oral and inhaled asthma medications. Arch Intern Med 1994,
154:1349–1352.
Sanguinetti CM: La terapia dell’asma stabile: gli outcome centrati sul
paziente. Multidiscip Resp Med 2007, 2(4):29–37.
Noonan G, Reiss TF, Shingo S, et al: Montelukast (MK-0476) maintains
long-term asthma control in adult and pediatric patients
(aged ≥ 6 years). Am J Respir Crit Care Med 1999, 159:A640.
Knorr B, Noonan G, McBurney J, et al: Evaluation of the long-term effect of
montelukast in adult (≥ 15 years) and pediatric (6- to 14-years) patients.
Eur Respir J 1999, 14:290S.
doi:10.1186/2049-6958-7-13
Cite this article as: Scaparrotta et al.: Montelukast versus inhaled
corticosteroids in the management of pediatric mild persistent asthma.
Multidisciplinary Respiratory Medicine 2012 7:13.